- Email: [email protected]
Serous cancer precursor evolution in the fallopian tube
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Abstracts / Gynecologic Oncology 130 (2013) e1–e169
none of the patients discontinued the study because of adverse events. Conclusions: The combination of aprepitant, ramosetron, and highdose dexamethasone represents an advance in treatment options for the prevention of CINV due to MEC over multiple cycles of chemotherapy.
doi:10.1016/j.ygyno.2013.04.117
Scientific Plenary VIII - Origins of Serous Cancers Tuesday, March, 12, 2013, 9:30 a.m. - 10:40 a.m. Concourse Hall (Los Angeles Convention Center) Moderators, Abstracts: 59-62: Blake Gilks, University of British Columbia, Vancouver, BC. Jamie Lesnock, MD, Mid Atlantic Gynecologic Oncology of Mon General Hospital, Morgantown, WV 59 A novel proteomic-based screening method for ovarian cancer using cervi- covaginal fluids: A window into the abdomen R. Rocconi1, L. Pannell1, D. Billheimer2, J. Blandford1, L. Schambeau1, M. Finan1. 1University of South Alabama-Mitchell Cancer Institute, Mobile, AL, 2University of Arizona, Tuscon, AZ. Objective: To develop a site-specific proteomic-based screening test for ovarian cancer using the mucus of the cervix and vagina. Although this location is counterintuitive, the sole purpose of the fallopian tube is to actively transport oocytes from the ovary to the endometrium. This active transport spills a protein-rich fluid that eventually drains down the uterus, through the cervix, and into the vagina. Coupled with this transport mechanism, emerging molecular data demonstrate that most ovarian cancers potentially originate within the fallopian tube itself. Methods: Cervicovaginal fluid samples were obtained during pelvic exams for liquid chromatography-mass spectrometry (LC-MS) evaluation of differences in proteomic sequencing between ovarian cancer patients and normal controls. Peptide selection was performed using “lasso” modeling, with penalty factor chosen by “leave-
one-out” cross-validation to select the most accurate set of predictors. A best subset regression analysis was used to determine the panel with the best detection of disease and highest penetrance across ovarian cancer samples. Results: A total of 83 consecutive patient samples were collected prospectively (33 ovarian cancer and 50 controls). Using LC-MS, 36 peptides demonstrated independent statistical significance for detecting ovarian cancer. Using statistical modeling, the protein panel that determined the best predictor for detecting ovarian cancer formed an ovarian cancer “fingerprint.” This fingerprint consists of 5 known proteins: serine proteinase inhibitor A1, periplakin, profilin1, apolipoprotein A1, and thymosin beta4-like protein. Thymosin beta4-like protein was “sentinel” in that it was only observed in ovarian cancer patients while being absent in all controls. These peptides have a rationale for carcinogenesis and demonstrate a significant increased probability of detecting ovarian cancer with their receiver operating characteristics curve having an AUC of 0.88 (P = 0.00001) (Figure). Conclusions: Using novel site-specific collection methods, we have statistically identified a group of peptides that detect ovarian cancer. Statistical modeling detected this ovarian cancer “fingerprint” with adequate sensitivity and specificity to warrant further evaluation in a larger cohort. Combining our results with emerging data suggesting that most ovarian cancers originate within the fallopian tube, this methodology has the potential to detect earlystage ovarian cancer in a screening test.
doi:10.1016/j.ygyno.2013.04.118
60 Serous cancer precursor evolution in the fallopian tube C. Crum1, G. Ning2, M. Herfs3, Y. Yamamoto4, F. McKeon2, W. Xian2. 1 Brigham and Women’s Hospital, Boston, MA, 2Jackson Laboratories, Farmington, CT, 3Brigham & Women’s Hospital, Boston, MA, 4A*STAR, Singapore, Singapore. Objective: Given the failure of screening programs in improving survival, the limited success of targeted therapy, and the absence of data supporting routine opportunistic prophylactic salpingectomy in healthy low-risk women, novel paradigms of ovarian cancer prevention are needed. The distal fallopian tube is implicated in the genesis of many of the most lethal high-grade serous carcinomas, and precursors (p53 signatures and tubal intraepithelial carcinomas) to these neoplasms have been proposed. Precisely how these entities emerge from the tubal mucosa and the specific cells targeted remain unclear. Because the distal tube harbors a unique mullerianmesothelial junction, we addressed the possibility that this junction harbored unique target epithelial cells. Methods: Embryonic derived epithelial cells from the cervix squamocolumnar junction were analyzed by array technology to identify embryonic-specific genes. Selected biomarkers were used to probe fallopian tubes to identify region-specific gene expression. Selected markers were then applied to a range of precursor lesions to identify gene expression linking these precursors to potential progenitor cells. Results: A series of embryonic markers identified a subpopulation of nonciliated cells in the distal oviduct. These markers, by both their presence/absence, were selectively expressed/not expressed in a majority of direct precursors (p53 signatures or serous tubal intraepithelial carcinomas) to high-grade serous cancer. The same markers were also expressed/not expressed in other secretory cell outgrowths (SCOUTs) that have not been described in significantly higher frequency in the tubes of women with ovarian cancer.
Abstracts / Gynecologic Oncology 130 (2013) e1–e169
e25
Conclusions: A specific immunophenotype identifies both a subpopulation of nonciliated epithelial cells in the normal distal oviduct and serous cancer precursors. This suggests that a certain population evolving during embryogenesis is a frequent if not exclusive target for clonal expansions, including some that could eventuate in malignancy. Regional differences in serous cancer precursor distribution could reflect the distribution of this population as well as genotoxic stimuli. Variations in the latter may explain the variable forms of clonal expansion seen in the oviduct. The link between the shared features of these early lesions, the relationship of some to serous cancer, and the role of the proximity of the distal tube to a mullerian-mesothelial junction as the underpinning of this process merit further study.
doi:10.1016/j.ygyno.2013.04.119
61 Brush cytology of the fallopian tube G. Linnemeier1, G. Sutton1, A. Moriarty2, M. Callahan1, H. Fornalik1, R. McCarthy2. 1St. Vincent Gynecologic Oncology, Indianapolis, IN, 2 St. Vincent Hospital, Indianapolis, IN. Objective: Recent evidence suggests that many high-grade “ovarian” serous carcinomas (HGSC) are associated with epithelial precursors in the fallopian tube (FT). Such tubal intraepithelial carcinomas are observed in salpingectomy specimens obtained at risk-reducing surgery in BRCA-positive women. The purpose of this study was to evaluate the cytomorphology of cells obtained from the FT. Methods: Women undergoing salpingo-oophorectomy (SO) for risk reduction or for pelvic masses were selected for study. Immediately after surgical removal, the FT was transected at its midpoint and a cytobrush was introduced into the lumen, advanced toward the fimbria, and withdrawn. The specimen was rolled onto a glass slide, fixed in 95% ethanol and stained with Papanicolaou stain. An expert cytopathologist examined the slides, and all cases had pathologic correlation. Results: 91 FTs from 58 patients (pts) were examined. Epithelial cells characteristic of the FT were identified in 87/91 (96%) specimens. In pts with benign disease and no personal or family history of breast cancer, atypia was reported in one of 19 FTs. Malignant or atypical cells were identified in 12/15 FTs from 8 pts with untreated HGSC and in 0 of 6 FTs from 3 pts treated with neoadjuvant chemotherapy. 5 pts undergoing prophylactic SO had known BRCA mutations at the time of surgery. Atypical cells, nuclear enlargement, or “naked” (stripped) nuclei were observed in 3/9 FTs in this high-risk group. Naked nuclei were observed in 22/58 pts (38%). These myoepithelial cells of stromal origin, previously described in association with proliferations of the breast, were observed in 11/14 FTs from 8 pts with breast cancer or a family history of breast cancer, 8/9 FTs from 6 pts with endometriosis, 6/8 FTs from 4 pts with HGSC, 2/2 FTs from 2 pts with other adenocarcinoma, and 2/3 FTs from 2 pts with benign findings. Conclusions: If a precursor lesion exists in the FT, a cytologic screening technique might be developed for women at risk for HGSC. This study demonstrates that adequate FT cytology specimens can be obtained at the time of SO. These findings suggest that cytologic study of the FT using hysteroscopy may be feasible. The nature of myoepithelial cells of stromal origin arising from the FT needs elucidation.
doi:10.1016/j.ygyno.2013.04.120
62 The impact of tubal sterilization techniques on the risk of serous ovarian and primary peritoneal carcinoma: A Rochester Epidemiology Project (REP) study C. Lessard-Anderson, R. Molitor, J.St. Sauver, K. Steckelberg, A. Weaver, J. Bakkum-Gamez, S. Dowdy, B. Cliby. Mayo Clinic, Rochester, MN. Objective: Evidence is emerging that implicates tubal epithelium as the source of serous epithelial ovarian cancer (EOC). We aimed to determine the impact of tubal sterilization, specifically excisional methods, on subsequent development of serous EOC or primary peritoneal cancer (PPC). Methods: This was a population-based case-control study utilizing individuals residing in Olmsted County, Minnesota. Cases included females diagnosed with either serous EOC or PPC between 1/1/1966 and 12/31/2010. Controls consisted of age-matched females seen in the same time period without either diagnosis identified from Olmsted County using the resources of the Rochester Epidemiology Project (REP). Cases were matched 1:2 with controls. Reproductive, surgical, and medical data prior to the index date were abstracted. Results: Over the 45-year period, 194 cases of serous EOC and PPC (mean [SD] age, 61.4 [15.2] years) were diagnosed among Olmsted County residents. Cases were matched with 388 controls. Among cases, 7.2% had a history of tubal sterilization compared to 11.6% of the controls. The adjusted overall risk of serous EOC or PPC was lower after any tubal sterilization (odds ratio [OR] 0.58; 95% CI 0.29-1.14; P = 0.11). Cases had a lower rate of excisional tubal sterilization compared to controls (2.6% vs 6.2%, respectively). The risk of serous EOC and PPC
Abstracts / Gynecologic Oncology 130 (2013) e1–e169
none of the patients discontinued the study because of adverse events. Conclusions: The combination of aprepitant, ramosetron, and highdose dexamethasone represents an advance in treatment options for the prevention of CINV due to MEC over multiple cycles of chemotherapy.
doi:10.1016/j.ygyno.2013.04.117
Scientific Plenary VIII - Origins of Serous Cancers Tuesday, March, 12, 2013, 9:30 a.m. - 10:40 a.m. Concourse Hall (Los Angeles Convention Center) Moderators, Abstracts: 59-62: Blake Gilks, University of British Columbia, Vancouver, BC. Jamie Lesnock, MD, Mid Atlantic Gynecologic Oncology of Mon General Hospital, Morgantown, WV 59 A novel proteomic-based screening method for ovarian cancer using cervi- covaginal fluids: A window into the abdomen R. Rocconi1, L. Pannell1, D. Billheimer2, J. Blandford1, L. Schambeau1, M. Finan1. 1University of South Alabama-Mitchell Cancer Institute, Mobile, AL, 2University of Arizona, Tuscon, AZ. Objective: To develop a site-specific proteomic-based screening test for ovarian cancer using the mucus of the cervix and vagina. Although this location is counterintuitive, the sole purpose of the fallopian tube is to actively transport oocytes from the ovary to the endometrium. This active transport spills a protein-rich fluid that eventually drains down the uterus, through the cervix, and into the vagina. Coupled with this transport mechanism, emerging molecular data demonstrate that most ovarian cancers potentially originate within the fallopian tube itself. Methods: Cervicovaginal fluid samples were obtained during pelvic exams for liquid chromatography-mass spectrometry (LC-MS) evaluation of differences in proteomic sequencing between ovarian cancer patients and normal controls. Peptide selection was performed using “lasso” modeling, with penalty factor chosen by “leave-
one-out” cross-validation to select the most accurate set of predictors. A best subset regression analysis was used to determine the panel with the best detection of disease and highest penetrance across ovarian cancer samples. Results: A total of 83 consecutive patient samples were collected prospectively (33 ovarian cancer and 50 controls). Using LC-MS, 36 peptides demonstrated independent statistical significance for detecting ovarian cancer. Using statistical modeling, the protein panel that determined the best predictor for detecting ovarian cancer formed an ovarian cancer “fingerprint.” This fingerprint consists of 5 known proteins: serine proteinase inhibitor A1, periplakin, profilin1, apolipoprotein A1, and thymosin beta4-like protein. Thymosin beta4-like protein was “sentinel” in that it was only observed in ovarian cancer patients while being absent in all controls. These peptides have a rationale for carcinogenesis and demonstrate a significant increased probability of detecting ovarian cancer with their receiver operating characteristics curve having an AUC of 0.88 (P = 0.00001) (Figure). Conclusions: Using novel site-specific collection methods, we have statistically identified a group of peptides that detect ovarian cancer. Statistical modeling detected this ovarian cancer “fingerprint” with adequate sensitivity and specificity to warrant further evaluation in a larger cohort. Combining our results with emerging data suggesting that most ovarian cancers originate within the fallopian tube, this methodology has the potential to detect earlystage ovarian cancer in a screening test.
doi:10.1016/j.ygyno.2013.04.118
60 Serous cancer precursor evolution in the fallopian tube C. Crum1, G. Ning2, M. Herfs3, Y. Yamamoto4, F. McKeon2, W. Xian2. 1 Brigham and Women’s Hospital, Boston, MA, 2Jackson Laboratories, Farmington, CT, 3Brigham & Women’s Hospital, Boston, MA, 4A*STAR, Singapore, Singapore. Objective: Given the failure of screening programs in improving survival, the limited success of targeted therapy, and the absence of data supporting routine opportunistic prophylactic salpingectomy in healthy low-risk women, novel paradigms of ovarian cancer prevention are needed. The distal fallopian tube is implicated in the genesis of many of the most lethal high-grade serous carcinomas, and precursors (p53 signatures and tubal intraepithelial carcinomas) to these neoplasms have been proposed. Precisely how these entities emerge from the tubal mucosa and the specific cells targeted remain unclear. Because the distal tube harbors a unique mullerianmesothelial junction, we addressed the possibility that this junction harbored unique target epithelial cells. Methods: Embryonic derived epithelial cells from the cervix squamocolumnar junction were analyzed by array technology to identify embryonic-specific genes. Selected biomarkers were used to probe fallopian tubes to identify region-specific gene expression. Selected markers were then applied to a range of precursor lesions to identify gene expression linking these precursors to potential progenitor cells. Results: A series of embryonic markers identified a subpopulation of nonciliated cells in the distal oviduct. These markers, by both their presence/absence, were selectively expressed/not expressed in a majority of direct precursors (p53 signatures or serous tubal intraepithelial carcinomas) to high-grade serous cancer. The same markers were also expressed/not expressed in other secretory cell outgrowths (SCOUTs) that have not been described in significantly higher frequency in the tubes of women with ovarian cancer.
Abstracts / Gynecologic Oncology 130 (2013) e1–e169
e25
Conclusions: A specific immunophenotype identifies both a subpopulation of nonciliated epithelial cells in the normal distal oviduct and serous cancer precursors. This suggests that a certain population evolving during embryogenesis is a frequent if not exclusive target for clonal expansions, including some that could eventuate in malignancy. Regional differences in serous cancer precursor distribution could reflect the distribution of this population as well as genotoxic stimuli. Variations in the latter may explain the variable forms of clonal expansion seen in the oviduct. The link between the shared features of these early lesions, the relationship of some to serous cancer, and the role of the proximity of the distal tube to a mullerian-mesothelial junction as the underpinning of this process merit further study.
doi:10.1016/j.ygyno.2013.04.119
61 Brush cytology of the fallopian tube G. Linnemeier1, G. Sutton1, A. Moriarty2, M. Callahan1, H. Fornalik1, R. McCarthy2. 1St. Vincent Gynecologic Oncology, Indianapolis, IN, 2 St. Vincent Hospital, Indianapolis, IN. Objective: Recent evidence suggests that many high-grade “ovarian” serous carcinomas (HGSC) are associated with epithelial precursors in the fallopian tube (FT). Such tubal intraepithelial carcinomas are observed in salpingectomy specimens obtained at risk-reducing surgery in BRCA-positive women. The purpose of this study was to evaluate the cytomorphology of cells obtained from the FT. Methods: Women undergoing salpingo-oophorectomy (SO) for risk reduction or for pelvic masses were selected for study. Immediately after surgical removal, the FT was transected at its midpoint and a cytobrush was introduced into the lumen, advanced toward the fimbria, and withdrawn. The specimen was rolled onto a glass slide, fixed in 95% ethanol and stained with Papanicolaou stain. An expert cytopathologist examined the slides, and all cases had pathologic correlation. Results: 91 FTs from 58 patients (pts) were examined. Epithelial cells characteristic of the FT were identified in 87/91 (96%) specimens. In pts with benign disease and no personal or family history of breast cancer, atypia was reported in one of 19 FTs. Malignant or atypical cells were identified in 12/15 FTs from 8 pts with untreated HGSC and in 0 of 6 FTs from 3 pts treated with neoadjuvant chemotherapy. 5 pts undergoing prophylactic SO had known BRCA mutations at the time of surgery. Atypical cells, nuclear enlargement, or “naked” (stripped) nuclei were observed in 3/9 FTs in this high-risk group. Naked nuclei were observed in 22/58 pts (38%). These myoepithelial cells of stromal origin, previously described in association with proliferations of the breast, were observed in 11/14 FTs from 8 pts with breast cancer or a family history of breast cancer, 8/9 FTs from 6 pts with endometriosis, 6/8 FTs from 4 pts with HGSC, 2/2 FTs from 2 pts with other adenocarcinoma, and 2/3 FTs from 2 pts with benign findings. Conclusions: If a precursor lesion exists in the FT, a cytologic screening technique might be developed for women at risk for HGSC. This study demonstrates that adequate FT cytology specimens can be obtained at the time of SO. These findings suggest that cytologic study of the FT using hysteroscopy may be feasible. The nature of myoepithelial cells of stromal origin arising from the FT needs elucidation.
doi:10.1016/j.ygyno.2013.04.120
62 The impact of tubal sterilization techniques on the risk of serous ovarian and primary peritoneal carcinoma: A Rochester Epidemiology Project (REP) study C. Lessard-Anderson, R. Molitor, J.St. Sauver, K. Steckelberg, A. Weaver, J. Bakkum-Gamez, S. Dowdy, B. Cliby. Mayo Clinic, Rochester, MN. Objective: Evidence is emerging that implicates tubal epithelium as the source of serous epithelial ovarian cancer (EOC). We aimed to determine the impact of tubal sterilization, specifically excisional methods, on subsequent development of serous EOC or primary peritoneal cancer (PPC). Methods: This was a population-based case-control study utilizing individuals residing in Olmsted County, Minnesota. Cases included females diagnosed with either serous EOC or PPC between 1/1/1966 and 12/31/2010. Controls consisted of age-matched females seen in the same time period without either diagnosis identified from Olmsted County using the resources of the Rochester Epidemiology Project (REP). Cases were matched 1:2 with controls. Reproductive, surgical, and medical data prior to the index date were abstracted. Results: Over the 45-year period, 194 cases of serous EOC and PPC (mean [SD] age, 61.4 [15.2] years) were diagnosed among Olmsted County residents. Cases were matched with 388 controls. Among cases, 7.2% had a history of tubal sterilization compared to 11.6% of the controls. The adjusted overall risk of serous EOC or PPC was lower after any tubal sterilization (odds ratio [OR] 0.58; 95% CI 0.29-1.14; P = 0.11). Cases had a lower rate of excisional tubal sterilization compared to controls (2.6% vs 6.2%, respectively). The risk of serous EOC and PPC